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Myeloma groupBORTEZOMIB THALIDOMIDE ANDDEXAMETHASONE (VTD21) 21 day cycleINDICATIONSInduction treatment of adults with previously untreated multiple myeloma, who are eligiblefor high-dose chemotherapy with haematopoietic stem cell transplantation [NICE TA311].Appropriate therapy for relapsed or refractory multiple myeloma in patients who are atsecond or more relapse and who have not received prior bortezomib based therapy.TREATMENT INTENTDisease modificationGENERAL PRE-ASSESSMENT1. Ensure all the following staging investigations are done:o FBC & filmo Clotting screeno U&Eso LFTso Calciumo Albumino Uric acido CRPo Baseline random blood glucose levelo Virology : HIV, Hepatitis B (including core antibody), and Hepatitis Co Calculated creatinine clearance (CrCl), urine protein/ creatinine ratioo Electrophoresis and immunofixation for quantitation of serum paraprotein andimmunoglobulinso Serum free light chain assay (Freelite)o β2 microglobulino LDHo Myeloma FISH should be performed in all patients at diagnosis, and in selected patients atrelapse/progression to help guide treatment decisions Samples should be sent to WessexRegional Genetics Laboratory (address below)o Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle.o Group and saveo Imaging as per NICE/network guidance and clinical presentationo Bone marrow aspirate and trephine (with immunophenotyping for kappa/lambda ifappropriate)Wessex Regional Genetic LaboratorySalisbury NHS Foundation TrustThis is a controlled document and therefore must not be changedMM.7Authorised by Myeloma lead Dr. Karthik RamasamyJune 2022VTD 21 day cycle1 of 8V. 1.9

Myeloma groupSalisbury District HospitalSalisburyWiltshireSP2 8BJ2.3.4.5.6.7.Additional Investigationso Plasma viscosity if hyperviscosity suspectedo If allogeneic transplant an option: Tissue typing of patient and siblings and CMV serologyConsent - ensure patient has received adequate verbal and written information regarding theirdisease, treatment and potential side effects. Document in medical notes all information thathas been given.Fertility - all patients should be offered fertility advice, as appropriate.Hydration - fluid intake of at least 3 litres /day should be attempted.Document patient’s height and weight, dose on actual body weight.Document patient’s performance statusTreatment must be agreed at the relevant MDT.REGIMEN SPECIFIC PRE -ASSESMENT1. Evaluate for presence of neuropathy. This is usually done by clinical assessment althoughnerve conduction studies may be useful in occasional patients to document the extent ofneurological damage prior to treatment with bortezomib2. The conditions of the Thalidomide Celgene Pregnancy Prevention Programme must befulfilled for all male and female patients. Prescribing and dispensing of thalidomide must bein line with the Pregnancy Prevention Programme3. Clinical assessment of thrombo-embolic risk4. Baseline lying and standing blood pressure should be recorded prior to administration ofcycle #1DRUG REGIMENBortezomib1.3 mg/m2 given S/C bolusDays 1, 4, 8 and 11Thalidomide50 -100 mg PO (preferably nocte)Daily on days 1 to 21Start at 50mg and considerincreasing the dose as toleratedDexamethasone20 mg PO once dailyDays 1, 2, 4, 5, 8, 9, 11 and 12 i.e. day of and day after eachbortezomib doseAt least 72 hours should elapse between consecutive doses of bortezomib.Bortezomib can also be administered weekly on days 1, 8 and 15 in a 21 days cycle in selectedpatients.If neurotoxicity precludes completing planned therapy, consider completing the intended number ofVTD cycles after the autologous transplant.This is a controlled document and therefore must not be changedMM.7Authorised by Myeloma lead Dr. Karthik RamasamyJune 2022VTD 21 day cycle2 of 8V. 1.9

Myeloma groupCYCLE FREQUENCYRepeat every 21 days.Allowable number of doses is as follows 24 doses for transplant eligible patients (first line therapy) 32 doses at (first) relapseDOSE MODIFICATIONSHaematological toxicityBORTEZOMIB:Thrombocytopenia due to bortezomib is transient and very rarely causes significant bleeding. Ifbaseline platelet count is 70, then the risk of severe thrombocytopenia is very lowIn such patients, FBC should be checked only at the start of the cycle and does not need to berepeated before each dose.In patients with platelets 70 at the start of each cycle, FBC should be checked before each dose,bortezomib should be withheld until FBC is through and the dose omitted if the platelets are 25unless thrombocytopenia is thought to be mainly due to marrow infiltration by myeloma. In thatscenario, consider proceeding with treatment along with platelet transfusion support.In all other circumstances, if these levels are not reached, then treatment should be withheld andsubsequent doses reduced by 25% (i.e. from 1.3 mg/m2 to 1.0 mg/m2 or from 1.0 mg/m2 to 0.7mg/m2).Peripheral neuropathyBORTEZOMIB:If there are symptoms of peripheral neuropathy, the dose reduction schedule must be invoked (seebelow). The drug should be stopped if symptoms or signs progress despite this.Severity of neuropathyG1 with no pain or loss of functionG1 with pain or G2G2 with pain or G3G4 and/or severe autonomic neuropathyDose modificationNoneReduce to 1.0 mg/m2 or reduce treatmentschedule to 1.3 mg/m2 once per week ifcurrently is twice per weekWithhold treatment until symptoms of toxicityhave resolved. When toxicity resolves, reinitiate at 0.7 mg/m2 once per week.DiscontinueTHALIDOMIDE:Thalidomide should be stopped or dose reduced if there are symptoms of progressive peripheralneuropathy causing functional disability (grade 2 or above). Consider cautious re-introduction ofthalidomide at a dose of 50mg daily if symptoms resolve to grade 1 or better after a two-week gapSubsequent cautious dose escalation should be considered if symptoms permit. Switching toCyBorDex is a reasonable alternative.This is a controlled document and therefore must not be changedMM.7Authorised by Myeloma lead Dr. Karthik RamasamyJune 2022VTD 21 day cycle3 of 8V. 1.9

Myeloma groupRenal & Hepatic impairment:BORTEZOMIB:Renal.Clinical decision if GFR 20ml/minIn dialysis patients, give after dialysisHepaticBili 1.5 x ULN: reduce to 0.7 mg/m2 inthe first treatment cycle. Consider a doseescalation to 1.0 mg/m2, or a further dosereduction to 0.5 mg/m2 in subsequentcycles, based on patient tolerability.THALIDOMIDE:RenalNo dose reduction necessaryHepaticNo dose reduction necessaryINVESTIGATIONS (at the beginning of each cycle) Urine pregnancy testing for pre-menopausal women younger than 55 before each cycle.FBC, U&Es, LFTs, Ca2 Ig's, paraprotein, usually monthly after first 2 months, Freelite assay if appropriate.Consider bone marrow assessment after four cycles for non-secretory Myeloma.Clinical assessment of neuropathy should be undertaken and documented prior to eachcycle.Blood pressure (consider checking for postural drop if symptomatic)Consider blood glucose monitoring in patients with diabetes and those with signs of glucoseintoleranceCONCURRENT MEDICATIONS Allopurinol 300 mg daily for 7 days for cycle 1 only.Prophylactic aciclovir 200 mg TDS (consider reducing to 200mg BD if CrCl 10ml/min) forthe duration of treatment and 3 months post therapy.Consider prophylactic fluconazole 50mg ODConsider prophylactic co-trimoxazole 960mg OD on M/W/F if heavily pre-treated orprevious autograft. Consider prophylactic levofloxacin 500mg od for 12 weeks (cycles 1-4) Proton Pump Inhibitor or H2 antagonist at clinician’s discretionThromboprophylaxis/anticoagulation- see VTE section belowBone protection as per NSSG Bone Protection protocol MM.3Patients on bortezomib should be closely monitored if on CYP3A4-inhibitors (e.g. ketoconazole,ritonavir). The concomitant use of bortezomib with strong CYP3A4-inducers (rifampicin,carabamazepine, phenytoin, phenobarbital, and St John’s wort) is not recommended as efficacymay be reduced.This is a controlled document and therefore must not be changedMM.7Authorised by Myeloma lead Dr. Karthik RamasamyJune 2022VTD 21 day cycle4 of 8V. 1.9

Myeloma groupExtravasation risk:Irritant: bortezomibEMETIC RISKLowADVERSE EFFECTS/REGIEMN SPECIFIC COMPLICATIONS Teratogenic: The Pregnancy Prevention Programme must be observed for all male andfemale patients. Prescribing and dispensing of thalidomide must be in line with the pregnancyprevention programme. Peripheral neuropathy: Patients should be advised to report pain hypersensitivity prickling,numbness and paraesthesia. If these occur see above dose reductions and consider use ofAmitriptyline, Gabapentin and Pain Team referral. Neuropathy assessment tools are availablein DTU. Caution in patients with existing peripheral neuropathy Venous thromboembolism (VTE): There is an increased risk of thrombosis with thalidomide.Unless the patient is thought to be at high-risk of bleeding (and this risk exceeds the risk ofVTE), some form of VTE prophylaxis is recommended as follows:1. Prophylactic low-molecular weight heparin OR2. Prophylactic NOAC e.g. apixaban 2.5mg bd (preferred)Aspirin can be appropriate for patients with no additional risk factors for thrombosis. It isgenerally not preferred for higher-risk patients with additional risk factorsIf VTE occurs, thalidomide can be continued and the patient should be fully anticoagulatedaccording to standard guidelines Dizziness and orthostatic hypotension: Patients should be advised that Bortezomib maycause orthostatic hypotension and that they should sit upright for a few minutes prior tostanding up from a recumbent position. Caution in patients with history of syncope, receivingmedications associated with hypotension and patients who are dehydrated. Management oforthostatic/postural hypotension may include adjustment of antihypertensive medicinalproducts, rehydration or administration of mineralocorticosteroids and/or sympathomimetics.Patients should be instructed to seek medical advice if they experience symptoms of dizziness,light-headedness or fainting spells. Patients who experience dizziness or low blood pressuremay benefit from 500ml intravenous 0.9% sodium chloride with each dose of bortezomib. Gastrointestinal: Nausea, diarrhoea, vomiting and constipation are very common and ileushas been reported. Drowsiness, somnolence and sedation: Take the thalidomide dose at night time.Thalidomide may potentiate the drowsiness caused by alcohol and other sedative medication.If affected, patients should be instructed not to drive cars, use machinery or perform hazardoustasks whilst taking thalidomide. Skin toxicity: in the event of toxic skin reactions such as Stevens-Johnson syndrome,thalidomide should be discontinued permanently.This is a controlled document and therefore must not be changedMM.7Authorised by Myeloma lead Dr. Karthik RamasamyJune 2022VTD 21 day cycle5 of 8V. 1.9